Endothelial Adenine Overload as a Mechanistic Driver of Cardiotoxicity in Type 2 Diabetes

People living with type 2 diabetes mellitus (T2DM) are twice as likely to develop and die from cardiovascular disease, including myocardial infarction and heart failure (HF). HF is a clinical syndrome defined by symptoms resulting from structural and/or functional cardiac abnormalities that ultimately reduce cardiac output and/or elevate intracardiac pressures. The objective of this study is to define the mechanism by which adenine accumulation in the heart contributes to HF in T2DM, and to determine whether inhibition of adenine production can prevent diabetes-induced cardiac dysfunction. Human heart tissues were analyzed by spatial metabolomics to assess adenine localization in non-diabetic and diabetic patients. Multi-modal analyses using autofluorescence to identify coronary vessels were overlaid with H 2 g/kg in vivo) or vehicle. Using the Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes cohort, human heart samples, and mouse models, we found that the urine adenine/creatinine ratio (UAdCR) was associated with incident HF after adjustment for clinical risk factors. Spatial metabolomics demonstrated increased adenine accumulation in the coronary vessels of diabetic human and mouse hearts. Adenine treatment for 24 hours reduced viability of diabetic H9c2 and HUVEC cells (MTT assay) and increased cell death (PI staining). In vivo, adenine levels initially decreased slightly in heart and kidney, then rose markedly after two weeks, coinciding with echocardiographic evidence of worsening cardiac function at week 3. Adenine administration in mice and cells impaired removal of damaged mitochondria (mitophagy), significantly reduced mitochondrial inner membrane protein Mic60 levels, and increased the number of structurally abnormal mitochondria in human diabetic hearts with HF, suggesting altered cardiac bioenergetics. All deleterious effects were reversed by the adenine-production inhibitor MTDIA. MTDIA prevented adenine accumulation in diabetic hearts and restored cardiac function, without altering blood glucose or body weight. These findings indicate that endogenous adenine, reflected by UAdCR, predicts HF incidence in T2DM and that adenine accumulation directly contributes to diabetes-induced HF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.